MAGL is the principal enzyme responsible for the in vivo degradation of 2-arachidonoyl glycerol (2-AG), an endogenous ligand of the cannabinoid receptors (e.g., CB1 and CB2). See e.g., Patel, J. Z. et al., “Loratadine analogues as MAGL inhibitors,” Bioorg. Med. Chem. Lett., 2015, 25(7):1436-42; Mechoulam, R. et al., “Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors” Biochem. Pharmacol., 50 (1995), 83-90; Sugiura, T. et al., “2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain,” Biochem. Biophys. Res. Commun., 215 (1995), 89-97.
There continues to be a need for alternative MAGL inhibitors.